Newly synthesized (R)-carvone-derived 1,2,3-triazoles: structural, mechanistic, cytotoxic and molecular docking studies

Abstract

In the current study, natural (R)-carvone was used as starting material for the efficient synthesis of several 1,2,3-triazole derivatives. The produced products were obtained in good yields and characterized by ¹H and ¹³C NMR and HRMS analysis. The newly synthesized monoterpenic 1,2,3-triazole 4 and derivatives were analyzed by viability tests (MTT) for their cytotoxic activity against three human cancer cells. Product 5 showed a medium antitumor activity, for which the IC₅₀ values against selected cells HT-1080, A-549 and MCF-7 were 29.25 μM, 31.62 μM and 26.02 μM, respectively. The regioselectivity of the condensation reaction and the molecular structure of the title compounds were determined by Density Functional Theory (DFT) using B3LYP calculations at 6-311 + G(d,p) level. The orbitals HOMO and LUMO were studied to determine the electronic properties of the synthesized compounds. In addition, the global reactivity indices were used to explain the regioselectivity for the formation of compound 6, and the theoretical results agree well with the experimental results. Molecular docking and molecular dynamics confirmed the empirical test results and confirmed the stability of the complex during inhibition of the anti-apoptotic protein for killing cancer cells.

Communicated by Ramaswamy H. Sarma

Graphical abstract

Keywords:

• (R)-Carvone
• 123-triazole
• Click chemistry
• Regioselectivity
• DFT calculation
• Molecular docking

Acknowledgements

We are grateful to Cadi Ayyad University and Chouaïb Doukkali University for providing financial support.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Figure 7. Complex RMSD from the starting structure as a function of simulation time. a: 06-Bcl-2 complex, b: 05-Bcl-2 complex, c: 04-Bcl-2 complex, α-carbon atom RMSD, the backbone RMSD and of all heavy atoms RMSD.

Figure 8. α-carbon atom RMSF values (Å) as a function of the residue number, during the entire simulation.

Figure 9. The radius of gyration of the solute as a function of simulation time, a: 06-Bcl-2 complex, b: 05-Bcl-2 complex, c: 04-Bcl-2 complex, d: Ref-Bcl-2 complex.

Figure 10. Number of hydrogen bonds in the solute as a function of simulation time, a: 06-Bcl-2 complex, b: 05-Bcl-2 complex, c: 04-Bcl-2 complex, d: Ref-Bcl-2 complex.